Introduction

As early as the 1700’s, it was observed that the potential of articular cartilage for intrinsic regeneration was minimal. Even very small cartilage defects cannot re-establish their essential low friction surface and tend to degrade further over time and a consequence of this inadequacy is osteoarthritis/OA, a chronic, degenerative joint disorder. Osteoarthritis is the fastest growing global health problem, with a total joint replacement being the only effective treatment for patients with end stage osteoarthritis. Many groups world-wide are examining the use of multiple stem cell/progenitor cells types to repair cartilage defects and/or modulate inflammation to promote healing in the osteoarthritic joint; however, little efficacy in promoting cartilage repair, or reducing patient symptoms over temporary treatments such as micro-fracture has been observed. One potential reason behind this lack of efficacy in clinical study results could be derived from the heterogeneity between patients, cell sources and even within cell populations (within a given patient) highlighting our need for more basic research into these progenitor and stem cell populations and their application in the treatment of osteoarthritis.

Content

Unfortunately this lack of evidence based research (both basic and clinical) has not stopped clinics from offering unfounded and unregulated cell therapies including ‘stem cell therapies’ for numerous chronic diseases. Many of the clinics that offer these services, target patients suffering from cartilage injury and/or osteoarthritis as there are currently no Health Canada or FDA approved therapeutics to treat this disease. While Health Canada has introduced a moratorium on these unapproved therapies and the FDA is pursuing injunctions against a number of clinics in the US, many clinics are still offered unfounded cell therapies to patients throughout North America.

At the present time, the limited amount of high quality published clinical research on these therapies, does not support the efficacy of these cell therapies for the treatment of osteoarthritis. In this presentation, I will discuss current cell therapies being offered as well the results of clinical and pre-clinical studies into the potential use of purified and characterized stem/progenitor cell populations for the treatment of cartilage injury and/or osteoarthritis.

While I believe that cell therapies including stem cell based approaches have promise for treating chronic degenerative conditions such as osteoarthritis, it is essential that we develop a better understanding of risks vs. benefits as well as the mechanisms underlying these therapies before they are offered to patients. Providing therapies not supported by strong basic and clinical evidence not only puts patients at risk, but may also irreparably damage the credibility of the field of regenerative medicine and our ability to translate evidence based therapies into the clinic.

Overall, as a field we require a deeper understanding of the role of tissue resident and exogenously delivered stem cells within the arthritic joint and base future cellular therapeutic approaches on a strong foundation of basic and pre-clinical science. Developing an effective disease-modifying therapy for osteoarthritis that uses patient-derived stem cells or that results in the patient’s own tissues repairing themselves would result in a paradigm shift in how precision medicine is utilized and delivered.

Introduction

Knee pain effects 25% of individuals over age 55, and is most commonly due to osteoarthritis, although other etiologies can occur [1]. For many of these patients, their arthritis is too advanced for arthroscopy but too premature for arthroplasty. This leaves many patients in a grey zone where no good surgical treatments remain. Furthermore, even well indicated total knee arthroplasty outcomes result in persistent knee pain in 10-34% of cases [2]. Therefore, there is a large unmet need to help understand and treat knee pain outside of the structural abnormalities that is typically the focus for surgeons. Through collaborating with other medical fields and basic scientists, translational research can further our understanding, and eventually our treatment practices, of the knee in the future.

Content

The knee is a unique joint that may be better perceived as an organ due to its complexity and multiple tissue types and should be treated as such. When taking this approach, it becomes reasonable to focus treatments based on the different tissue types including the following: hyaline articular cartilage, bone, synovial fluid, meniscus, ligaments, and the synovial lining. Along with this, the contributions to pain can be significant when considering the bone and synovial lining as the cartilage is aneural. This was demonstrated by Dye et al. when he had an arthroscopy performed on his knee while awake and demonstrated that the most sensitive area was in fact the synovium [3]. Therefore, while treating structural abnormalities in the knee are important, treating the knee environment such as the synovial fluid and synovium itself can be just as relevant. These treatments can result from collaboration with the field of Rheumatology and have included treatments such as injections of steroids for post-traumatic osteoarthritis and IL1-Ra for ACL injury [4-5]. Novel injections are also being investigated, such as ABT-981, an immunoglobin that targets IL-1α and IL-1β and intraarticular injections of Etanercept [6].

Treatment options for patients with knee pathologies, both surgical and non-surgical, continue to evolve. This is largely in part due to a greater volume of basic and translational science literature of the knee, especially our understanding of the role of synovial fluid and the healing potential of cartilage. This understanding has led to a recent interest in the role of biologic treatments. Biologics, including adipose tissue, platelet-rich plasma, hyaluronic acid (HA), bone marrow aspiration (BMAC), and amniotic fluid, have been relatively understudied in the treatment of knee pain [7]. These compounds have the potential to alter the synovial fluid environment and may have a clinical benefit intraoperatively and postoperatively. Early evidence of their efficacy has been shown in some studies. For example, the AMELIA study, which investigated HA in knee arthritis, showed symptom improvement [8]. Other current clinical trials include the investigation of intraarticular BMAC for the treatment of early arthritis. As we continue researching these compounds, basic scientists must collaborate with physicians to understand the mechanism behind these interventions by testing the effects of biologics on an in vitro knee environment and exploring compounds, namely growth factors and cytokines, that likely play a role.

While different structures in the knee can cause pain, the nerves themselves can be the source of pain as well. For example, anesthesiologists have shown that the addition of cooled radiofrequency ablation with corticosteroid injection improves outcomes in patients with symptomatic osteoarthritis [9]. Furthermore, pain management physicians have shown that Botox can be used in the treatment of patellofemoral pain syndrome [10].

The components of the knee, from articular cartilage to synovium, create a unique environment that works as a synergistic unit. However, when parts of this system go awry, pain often ensues. Therefore, physicians from different specialties, researchers, physical therapists, and other healthcare personnel need to collaborate to understand and treat the pain of this complex joint.

References

[1] Peat, G., R. McCarney, and P. Croft. "Knee Pain and Osteoarthritis in Older Adults: A Review of Community Burden and Current Use of Primary Health Care." Ann Rheum Dis 60, no. 2 (Feb 2001): 91-7.

[2] Beswick, A. D., V. Wylde, R. Gooberman-Hill, A. Blom, and P. Dieppe. "What Proportion of Patients Report Long-Term Pain after Total Hip or Knee Replacement for Osteoarthritis? A Systematic Review of Prospective Studies in Unselected Patients." BMJ Open 2, no. 1 (2012): e000435.

[3] Dye, S. F., G. L. Vaupel, and C. C. Dye. "Conscious Neurosensory Mapping of the Internal Structures of the Human Knee without Intraarticular Anesthesia." Am J Sports Med 26, no. 6 (Nov-Dec 1998): 773-7.

[4] Kraus, V. B., J. Birmingham, T. V. Stabler, S. Feng, D. C. Taylor, C. T. Moorman, 3rd, W. E. Garrett, and A. P. Toth. "Effects of Intraarticular Il1-Ra for Acute Anterior Cruciate Ligament Knee Injury: A Randomized Controlled Pilot Trial (Nct00332254)." Osteoarthritis Cartilage 20, no. 4 (Apr 2012): 271-8.

[5] Lattermann, C., C. A. Jacobs, M. Proffitt Bunnell, L. J. Huston, L. G. Gammon, D. L. Johnson, E. K. Reinke, et al. "A Multicenter Study of Early Anti-Inflammatory Treatment in Patients with Acute Anterior Cruciate Ligament Tear." Am J Sports Med 45, no. 2 (Feb 2017): 325-33.

[6] Wang, S. X., S. B. Abramson, M. Attur, M. A. Karsdal, R. A. Preston, C. J. Lozada, M. P. Kosloski, et al. "Safety, Tolerability, and Pharmacodynamics of an Anti-Interleukin-1alpha/Beta Dual Variable Domain Immunoglobulin in Patients with Osteoarthritis of the Knee: A Randomized Phase 1 Study." Osteoarthritis Cartilage 25, no. 12 (Dec 2017): 1952-61.

[7] Devitt, B. M., S. W. Bell, K. E. Webster, J. A. Feller, and T. S. Whitehead. "Surgical Treatments of Cartilage Defects of the Knee: Systematic Review of Randomised Controlled Trials." Knee 24, no. 3 (Jun 2017): 508-17.

[8] Navarro-Sarabia, F., P. Coronel, E. Collantes, F. J. Navarro, A. R. de la Serna, A. Naranjo, M. Gimeno, G. Herrero-Beaumont, and Amelia study group. "A 40-Month Multicentre, Randomised Placebo-Controlled Study to Assess the Efficacy and Carry-over Effect of Repeated Intra-Articular Injections of Hyaluronic Acid in Knee Osteoarthritis: The Amelia Project." Ann Rheum Dis 70, no. 11 (Nov 2011): 1957-62.

[9] Davis, T., E. Loudermilk, M. DePalma, C. Hunter, D. Lindley, N. Patel, D. Choi, et al. "Prospective, Multicenter, Randomized, Crossover Clinical Trial Comparing the Safety and Effectiveness of Cooled Radiofrequency Ablation with Corticosteroid Injection in the Management of Knee Pain from Osteoarthritis." Reg Anesth Pain Med 43, no. 1 (Jan 2018): 84-91.

[10] Chen, J. T., A. C. Tang, S. C. Lin, and S. F. Tang. "Anterior Knee Pain Caused by Patellofemoral Pain Syndrome Can Be Relieved by Botulinum Toxin Type a Injection." Clin Neurol Neurosurg 129 Suppl 1 (Feb 2015): S27-9.

Introduction

It’s an exciting time for Orthoregeneration research. New tools and technologies have provided further insight into the biology and repair of joint tissues than ever before. Despite much progress in recent decades, the quest to achieve “perfect” joint restoration in patients with damaged cartilage has remained elusive. Perhaps the answer has been lost somewhere in translation. It is a long journey from bench to bedside, and this talk will explore why and how effective collaboration between basic scientists and physicians is essential to achieve our common goals.

Content

By definition, translational research leverages basic biology to create and implement practices which improve patient care [1]. Recent major advances in gene and cell therapy highlight how successful scientist-physician collaborations have resulted in ground-breaking therapies for patients [2, 3] and key examples exist in the cartilage repair field as well [4, 5]. A formidable obstacle to such partnerships is a perceived cultural divide between basic scientists and clinicians, which is not unique to the Orthoregeneration field [6]. This culture divide can often be attributed to communication barriers, and as highlighted by Restifo and Phelan, basic scientists and clinicians often do not speak the same language. [6] Lengthy and highly specialized training result in the creation of unique dialects including specific terminology and acronyms. These dialects separate not only the scientists and clinicians, but can alienate them from the general public as well. Where then, do we begin to bridge this divide? First, defining shared challenges and objectives is a critical step forward.

Fundamentally, both clinicians and basic scientists in our field are working to restore joint function. It is well understood from both perspectives that joints are complicated organs involving multiple tissues under varied stresses. However, there is less agreement regarding which specific challenges are the greatest in the field. At the bench, basic scientists have recently made great progress towards understanding signaling mechanisms required for maintenance of a healthy chrondrocyte phenotype [7]. We have new answers for long standing questions regarding the origin and fate of intrinsic joint progenitor cell populations [8-11]. If, how and when this information could be leveraged to develop new therapies for patients remains unknown. From a basic science perspective these are all intriguing areas of research – but which would be the highest priority for clinicians? Further communication is needed to develop a consensus.

Recent data suggests that the traditional linear pipeline from bench to bedside may not be the most efficient path forward [12]. Basic scientists in the Orthoregeneration field need a clear understanding of which issues clinicians view as the greatest challenges. Inversely, clinicians could benefit from information about the knowledge and tools available from the bench. A refined circular or iterative model of translational research which fosters greater reciprocal interaction between scientists and clinicians could be the most productive path forward towards these efforts [12]. Furthermore, this model should strive to include not only experts in the Orthoregeneration field, but interdisciplinary collaborations as well [13].

In summary, several key challenges exist for basic science – clinical collaborations. There is great strength in the diversity between scientists and clinicians. To leverage this strength, the Orthoregeneration field must work towards speaking a common language, collectively defining challenges so that we may work together to achieve shared goals.

References

1. Woolf, S.H., The meaning of translational research and why it matters. Jama, 2008. 299(2): p. 211-213.

2. Mendell, J.R., et al., Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med, 2017. 377(18): p. 1713-1722.

3. June, C.H., et al., CAR T cell immunotherapy for human cancer. Science, 2018. 359(6382): p. 1361-1365.

4. Grande, D.A., et al., The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. Journal of Orthopaedic Research, 1989. 7(2): p. 208-218.

5. Brittberg, M., et al., Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. New england journal of medicine, 1994. 331(14): p. 889-895.

6. Restifo, L.L. and G.R. Phelan, The cultural divide: exploring communication barriers between scientists and clinicians. Disease models & mechanisms, 2011. 4(4): p. 423-426.

7. Sherwood, J., Osteoarthritis year in review 2018: biology. Osteoarthritis and Cartilage, 2019. 27(3): p. 365-370.

8. Li, L., et al., Superficial cells are self-renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice. The FASEB Journal, 2016. 31(3): p. 1067-1084.

9. Decker, R.S., et al., Cell origin, volume and arrangement are drivers of articular cartilage formation, morphogenesis and response to injury in mouse limbs. Developmental Biology, 2017. 426(1): p. 56-68.

10. Roelofs, A.J., et al., Joint morphogenetic cells in the adult mammalian synovium. Nature Communications, 2017. 8: p. 15040.

11. Fellows, C.R., et al., Characterisation of a divergent progenitor cell sub-populations in human osteoarthritic cartilage: the role of telomere erosion and replicative senescence. Scientific reports, 2017. 7: p. 41421.

12. Fudge, N., et al., Optimising Translational Research Opportunities: A Systematic Review and Narrative Synthesis of Basic and Clinician Scientists' Perspectives of Factors Which Enable or Hinder Translational Research. PloS one, 2016. 11(8): p. e0160475-e0160475.

13. Chao, H.-T., L. Liu, and H.J. Bellen, Building dialogues between clinical and biomedical research through cross-species collaborations. Seminars in cell & developmental biology, 2017. 70: p. 49-57.

Introduction

The cartilage repair field was the pioneer of biological approaches in the re-attainment of joint homeostasis, including the use of cells and tissue in joint surface repair. Why then are we still trying and failing to attain our goal whilst the rest of medicine surges ahead in harnessing the power of cells and genes in all areas of medicine from opthalmology to immunology and cancer? Was John Hunter correct in 1743?

Content

From the groundbreaking work of early pioneers in the cartilage repair field to the latest crop of therapies, we as a field are trying, and mostly not succeeding in our goal of repairing and regenerating cartilage. Cartilage repair pioneers led the way in understanding how cells and even tissues might be harvsted safely from living patients and stored or reused in the repair of cartilage defects.

This talk will explore the current state of the art in cell and gene therapies being developed globally for a variety of diseases and how the cartilage repair and joint preservation field might be able to learn from some of these developments and breakthroughs. The rapid expansion in the development of cell and gene therapies has allowed us to look at how therapies are developed and to make some fundamental changes to the way we think about collaboration between the various actors in this ecosystem. By starting with autologous products, we have brought the scientific, clinical and manufacturing steps much closer together with a common focus - the patient. This has allowed knowledge and experience to spill over from one group to the other, creating new ways of working to the benefit of our patients.

It is not just these groups that have had to change the way they work. Regulators, previously the keepers of the developmental and scientific application knowledge have had to lean into companies and academics in order to understand the rapidly developing field of Regenerative Medicine and the multitude of scientific adavnces being made at a blistering pace. By companies and academics assuming a new role of educators to the regulators, we have managed to build a much stronger relationship of trust with them and in so doing helped to advance their understanding, but also our ability to propose new approaches and therapies at a much faster rate with more uncertainties than previously before. By bringing the regulators on our journey of scientific discovery, we have empowered them to generally take a more risk balanced approach to regulation and review of advanced therapies, allowing patients to access them sooner than previously.

The relationship between academia and industry has also shifted thanks to the unique challenges of advanced therapies. No longer are the large pharma giants the masters of drug discovery and development. They have come to realise that the true innovation engines are in academia. Academia is the fertile ground of scientific breakthrough, but industry is the sunlight that allows it to blossom into therapies from which thousands of patients will benefit. Regen med has allowed industry and academia to find new ways of innovating in partnership. We will explore some of these examples and how patients have benefitted from this new found mutual understanding and respect.

Only by all players in the ecosystem working together to innovate for patients will we be able to improve how we address the challenges of repairing and regenerating the joint, and soon perhaps even preventing the degeneration occuring in the first place. This is an exciting time for our ecosystem and only by collaborating will we truly prove John Hunter wrong.

Introduction

Imaging of the joint has benefited greatly from new technologies to image morphology and function in many tissues[1, 2]. Conventional radiography has long been used to detect structural changes, including fractures, osseous erosions and joint space narrowing but is only sensitive to established morphologic changes at later disease stages[3]. MRI has become the benchmark for musculoskeletal imaging due to its ability to non-invasively evaluate soft tissue, articular and osseous structures. Additionally, advanced quantitative MRI techniques can provide unique cellular and microstructural information in several musculoskeletal soft tissues[4-7]. While MRI is unmatched in its ability to evaluate soft tissue and bone marrow pathology, it has some limitation for molecular imaging, particularly in osseous structures. Positron Emission Tomography (PET) offers incomparable ability to provide quantitative information about molecular and metabolic activity that often precedes structural and even biochemical changes[8]. In this session, several emerging PET applications for evaluation of numerous degenerative joint processes and features will be discussed. Additionally, the potential of combining this complementary PET information with established quantitative MRI methods with simultaneous PET-MRI will be presented.

Content

Imaging of Bone Metabolism

¹⁸F-NaF was first recognized as a bone-seeking agent in 1962[9] and has been approved for PET imaging by the food and drug administration (FDA) since 1972. Uptake of ¹⁸F-NaF is a function of osseous blood flow and reflects bone remodeling and has been shown to correlate with bone histomorphometry[10].

PET imaging with ¹⁸F-NaF provides a method to assess subchondral bone activity in the joint. Increased bone remodeling has been implicated as a mechanism of OA progression that affects not only bone but also adjacent tissues[11, 12]. Initial results have shown significantly different levels of ¹⁸F-NaF uptake in various bone tissue types as well as in subchondral bone pathology (bone marrow lesions, osteophytes, sclerosis) identified on MRI. Furthermore, high ¹⁸F-NaF uptake in subchondral bone did not always correspond to structural damage detected on MRI. Additionally, in patients with unilateral anterior cruciate ligament (ACL) tears, who have a known increased risk for developing accelerated OA, significantly increased ¹⁸F-NaF PET uptake has been observed in the subchondral bone of ACL-injured knee joints, compared with their uninjured contralateral knees[13]. As molecular changes often precede changes at the tissue level, these findings suggest increased bone activity detected with ¹⁸F-NaF PET may serve as a marker for early disease in this population.

¹⁸F-NaF PET bone information can be combined with MRI data for comprehensive whole-joint imaging. Increases in cartilage T_1ρ relaxation times, which are associated with a loss of cartilage GAG content, have been correlated with increased ¹⁸F-NaF uptake in the adjoining bone as well as reduced uptake in the nonadjoining compartments[14]. In a separate study of patients with unilateral ACL tears, a correlation was observed between increased ¹⁸F-NaF uptake measures of bone remodeling and increased T₂ values in adjacent cartilage, which is indicative of early collagen matrix breakdown[13]. This correlation was particularly pronounced in the deep layers of cartilage adjacent to the subchondral bone. This supports an interdependent relationship between bone and cartilage with early degenerative changes in one tissue having an effect on the neighboring tissue.

Imaging of Inflammation and Immune response

¹⁸F-FDG, an analog of glucose, is the most widely used PET radiotracer in clinical practice and can provide information about inflammatory processes occurring in the musculoskeletal system[15, 16]. FDG has been applied to study synovitis and the inflammatory component of bone marrow lesions (BMLs) in OA and RA. A diffuse increase in FDG uptake was seen in OA patients compared to healthy age-matched controls, which the authors attributed to the presence of synovitis in OA[17, 18]. FDG PET is also able to quantitatively image elevated glucose utilization in cells mounting an immune response. FDG uptake has been correlated with disease activity and C-reactive protein levels in Rheumatoid Arthritis (RA) patients[19]. Further, it has been used to evaluate the extent of whole body involvement in RA[20], clinical outcomes, and treatment efficacy in early RA patients undergoing DMARD therapy[21]. In addition to FDG PET, additional PET tracers may offer new molecular targets with greater sensitivity to inflammation. For example, ¹¹C-choline can target cellular proliferation[22] while ¹¹C-(R)-PK11195 targets proteins on activated macrophages and may offer more specific molecular marker of inflammation[23].

Imaging of Pain Generators

FDG PET has shown promising results in diagnosis for neuropathic pain. The main assumption of this approach is that the neuroinflammatory process in the painful nerve lesion may result in hypermetabolic activity, presenting as focally high FDG uptake in the PET image. Co-registration of the PET image with high-resolution MRI facilitates identification and localization of increased FDG uptake within nerve tissues. An animal study validated this assumption with a rat-model experiment and human studies have since shown the sensitivity of FDG to neuroinflammation at the site of impinged spinal nerves.

A more specific radioligand, 18F-FTC-146[24, 25], was recently introduced for PET-MRI with improved specificity to pain. 18F-FTC-146 specifically binds to sigma-1 receptors, a transmembrane protein that becomes increasingly expressed in the nervous system with many neurological diseases that cause neuropathic pain[25, 26]. 18F-FTC-146 PET-MRI of patients with complex regional pain syndrome showed that the imaging findings altered the pain management plan for 7 out of 8 patients, and change of therapy in two patients achieved a considerably improved pain-relief outcome[27].

Multimodality PET Imaging

While PET imaging is unmatched for molecular imaging, it needs the assistance of higher-resolution, anatomic information to localize these physiologic processes. It is most often combined with CT imaging, which is able to provide not only high resolution anatomic detail but also attenuation correction information for acquired PET data[28]. While PET/CT has become essential for evaluation of oncologic disease, its utility as a stand-alone modality for characterization of musculoskeletal disease (including cancers) has been limited, largely due to the unparalleled soft tissue contrast of MRI.

New integrated PET-MRI systems potentially provide a complete imaging modality for musculoskeletal imaging, combining simultaneous molecular and physiologic information from PET with the high spatial resolution and soft tissue contrast information of MRI to provide a superior level of anatomic and functional information. Other comparative advantages of PET-MRI include no additional ionizing radiation for anatomic localization and the ability of MRI to provide supplementary functional information such as DWI. Hybrid PET-MRI offer new opportunities to incorporate the molecular capabilities of nuclear imaging into studies of joint degradation.

References

1. Gold G, Shapiro L, Hargreaves B, Bangerter N. Advances in musculoskeletal magnetic resonance imaging. Topics in magnetic resonance imaging : TMRI. 2010;21(5):335-338.

2. Wilmot A, Gieschler S, Behera D, et al. Molecular imaging: an innovative force in musculoskeletal radiology. AJR Am J Roentgenol. 2013;201(2):264-277.

3. Roemer FW, Eckstein F, Hayashi D, Guermazi A. The role of imaging in osteoarthritis. Best practice & research Clinical rheumatology. 2014;28(1):31-60.

4. Wehrli FW, Song HK, Saha PK, Wright AC. Quantitative MRI for the assessment of bone structure and function. NMR Biomed. 2006;19(7):731-764.

5. Matzat SJ, Kogan F, Fong GW, Gold GE. Imaging strategies for assessing cartilage composition in osteoarthritis. Current rheumatology reports. 2014;16(11):462.

6. Kogan F, Haris M, Singh A, et al. Method for high-resolution imaging of creatine in vivo using chemical exchange saturation transfer. Magn Reson Med. 2014;71(1):164-172.

7. Englund EK, Rodgers ZB, Langham MC, Mohler ER, 3rd, Floyd TF, Wehrli FW. Measurement of skeletal muscle perfusion dynamics with pseudo-continuous arterial spin labeling (pCASL): Assessment of relative labeling efficiency at rest and during hyperemia, and comparison to pulsed arterial spin labeling (PASL). J Magn Reson Imaging. 2016.

8. Chaudhry AA, Gul M, Gould E, Teng M, Baker K, Matthews R. Utility of positron emission tomography-magnetic resonance imaging in musculoskeletal imaging. World J Radiol. 2016;8(3):268-274.

9. Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for bone scanning. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 1962;3:332-334.

10. Piert M, Zittel TT, Becker GA, et al. Assessment of porcine bone metabolism by dynamic [18F]-fluoride ion PET: correlation with bone histomorphometry. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2001;42(7):1091-1100.

11. Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nature reviews Rheumatology. 2012;8(11):665-673.

12. Hayami T, Pickarski M, Wesolowski GA, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004;50(4):1193-1206.

13. Kogan F, Fan AP, Black M, Hargreaves B, Gold G. Imaging of Bone Metabolism and Its Spatial Relationship with Cartilage Matrix Changes in ACL-Injured Patients. Orthopaedic Research Society 2018 Annual Meeting; 2018; New Orleans, LA.

14. Savic D, Pedoia V, Seo Y, et al. Imaging Bone-Cartilage Interactions in Osteoarthritis Using [18F]-NaF PET-MRI. Mol Imaging. 2016;15:1-12.

15. Etchebehere EC, Hobbs BP, Milton DR, et al. Assessing the role of (1)(8)F-FDG PET and (1)(8)F-FDG PET/CT in the diagnosis of soft tissue musculoskeletal malignancies: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2016;43(5):860-870.

16. Schelbert HR, Hoh CK, Royal HD, et al. Procedure guideline for tumor imaging using fluorine-18-FDG. Society of Nuclear Medicine. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 1998;39(7):1302-1305.

17. Nakamura H, Masuko K, Yudoh K, et al. Positron emission tomography with 18F-FDG in osteoarthritic knee. Osteoarthritis Cartilage. 2007;15(6):673-681.

18. Wandler E, Kramer EL, Sherman O, Babb J, Scarola J, Rafii M. Diffuse FDG shoulder uptake on PET is associated with clinical findings of osteoarthritis. AJR Am J Roentgenol. 2005;185(3):797-803.

19. Beckers C, Ribbens C, Andre B, et al. Assessment of disease activity in rheumatoid arthritis with (18)F-FDG PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2004;45(6):956-964.

20. Kubota K, Ito K, Morooka M, et al. Whole-body FDG-PET/CT on rheumatoid arthritis of large joints. Annals of nuclear medicine. 2009;23(9):783-791.

21. Roivainen A, Hautaniemi S, Mottonen T, et al. Correlation of 18F-FDG PET/CT assessments with disease activity and markers of inflammation in patients with early rheumatoid arthritis following the initiation of combination therapy with triple oral antirheumatic drugs. Eur J Nucl Med Mol Imaging. 2013;40(3):403-410.

22. Roivainen A, Parkkola R, Yli-Kerttula T, et al. Use of positron emission tomography with methyl-11C-choline and 2-18F-fluoro-2-deoxy-D-glucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium. Arthritis Rheum. 2003;48(11):3077-3084.

23. van der Laken CJ, Elzinga EH, Kropholler MA, et al. Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography. Arthritis Rheum. 2008;58(11):3350-3355.

24. James ML, Shen B, Nielsen CH, et al. Evaluation of sigma-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014;55(1):147-153.

25. Shen B, Behera D, James ML, et al. Visualizing Nerve Injury in a Neuropathic Pain Model with [(18)F]FTC-146 PET/MRI. Theranostics. 2017;7(11):2794-2805.

26. Zamanillo D, Romero L, Merlos M, Vela JM. Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol. 2013;716(1-3):78-93.

27. Yoon D, Cipriano P, Hjoernevik T, et al. Management of Complex Regional Pain Syndrome (CRPS) with [18F]FTC-146 PET/MRI. Paper presented at: Proceedings of International Society for Magnetic Resonance in Medicine2017; Hawaii.

28. Brady Z, Taylor ML, Haynes M, et al. The clinical application of PET/CT: a contemporary review. Australas Phys Eng Sci Med. 2008;31(2):90-109.

Acknowledgments

NIH Grant Funding: K99EB022634

Introduction

ACL tears are a common knee injury and are associated with an elevated risk of developing OA. Bone plays an important role in OA development, and bone mass has been shown in animal models and human studies to decrease immediately following injury before partially recovering. ACL transection models have confirmed this bone loss is driven by trabecular structure degradation, however, this has not been confirmed in humans due to limited in vivo image resolution. The recent development of high-resolution peripheral quantitative computed tomography (HR-pQCT) provides an unprecedented opportunity to longitudinal assess bone microarchitecture in the knee, and magnetic resonance imaging (MRI) complements this technology so that both hard and soft tissues can be simultaneously tracked. This allows, for example, the monitoring of bone marrow lesions, which commonly occur in post-traumatic knee injury, and we are particularly interested in early joint changes that may lead to long-term development of knee osteoarthritis.

The objective of this study was to establish bone microarchitectural changes in the human knee within the first year following a unilateral acute ACL tear, using HR-pQCT and MRI.

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METHODS: Participants with unilateral ACL tears (n=15, 22-44 years of age, 10 female and 5 male) were followed with HR-pQCT with up to four time points (baseline, +2 months, +4 months, +8months). The baseline measurement occurred within 6 weeks of injury. Both the ACL deficient and uninjured contralateral knees were imaged at 61μm isotropic voxel size (XtremeCTII, Scanco Medical). Bone microarchitecture was assessed up to 7.5 mm below the weight bearing surfaces of the medial and lateral tibia and femur. The subchondral bone plate (density, thickness), and trabecular bone (density, thickness, number, separation) were quantified. Longitudinal bone changes within each knee were assessed using quadratic temporal mixed effects models, which were compared to linear and intercept-only mixed effects models using chi-squared tests (level of significance: p<0.05). 95% confidence intervals for each model parameter were assessed using bootstrapping (200 samples with replacement). MRI captured regions of bone marrow lesions, and by multimodal image registration between HR-pQCT and MRI it was possible to establish the changes to bone microarchitecture that occur specifically in the BML region.

RESULTS: Bone loss occurred throughout the injured knee (-4.6% to -15.8%; Fig 1). Bone loss occurred in a non-linear manner, with loss occurring within the first 7 to 8 months post-injury before indicating the start of a recovery phase. The loss was driven by trabecular structure degradation as reflected by an increase in trabecular separation (6.4% to 10.6%) and decrease in number (-3.1% to -7.8%) of trabecular elements. The subchondral bone plate of the lateral femur significantly decreased in thickness (-9.0%). Regions of BMLs had accelerated microarchitectural adaptations compared to the rest of the knee. The contralateral knee was mostly unaffected.

CONCLUSION: Bone loss in the injured knee during the first year following ACL tears is driven by loss of trabecular elements. This likely cannot be reversed as for any future ‘recovery’ of bone mass there is no known mechanism to re-establish the original bone structure. Thus, permanent structural changes may persist, which indicates there may be a short window for intervention to reduce the risk of long-term OA development.

Acknowledgments

This study was funded by The Arthritis Society, SOG-15-226.

Introduction

Knee injuries are a common occurrence of sport participation and it has become increasing apparent that such injuries can have a lifelong consequence for the athlete. One of the most serious knee injuries is an anterior cruciate ligament (ACL) tear and this injury will be used throughout this talk to illustrate concepts pertaining to injury prevention or risk reduction.

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There is evidence to show that degenerative changes in the knee can occur early, within one to two years, after an anterior cruciate ligament (ACL) injury and that on average 50% of patients are estimated to develop disabling osteoarthritis in the longer term. Although there is some evidence that ACL reconstruction reduces the risk of osteoarthritis there is stronger evidence that it does little to protect the knee from long term degeneration. Associated damage which may occur to the menisci or articular surfaces, has also been shown to increase the risk of developing osteoarthritis. Therefore, injury prevention is key. Unfortunately, the rates of ACL injury are steadily increasing, particularly at the younger end of the age spectrum. Concerning new data also shows that rates of concomitant meniscal injuries have also substantially increased, and again the younger aged athlete is more susceptible. This increasing prevalence of meniscal involvement is of concern for long term knee health.

Fortunately, injury prevention programs can reduce the risk of both knee injuries and ACL injuries. Most programs have targeted female athletes and incorporate neuromuscular training interventions to address modifiable risk factors. Most evidence is available for ACL injury risk reduction in female athletes although there is emerging evidence for male athletes. It has been recommended that such programs should include a combination of plyometric, strength and balance training for at least 6 weeks with a minimum of 1 session per week. For optimal results training should take place both pre and in-season. Critical components for the success of such training programs have been shown to be age (younger athletes gaining most benefit), dosage (superior results with longer and more frequent training), exercise variation and verbal feedback. Including any one of these four components has been shown to reduce injury risk by 18%. Injury prevention programs additionally have the potential to reduce further medical costs, with cost analysis showing that the optimum implementation strategy is to target high risk athletes aged 12-25 years. For this group US$17,000 can be spent per participant on the program. However, perhaps one of the biggest challenges with injury prevention training programs is in their implementation. Regular compliance is a critical factor for injury risk reduction and barriers to high compliance have been therefore been investigated. Program design has been shown to be a key influencing factor with programs that contain sport specific tasks and less than 15 minutes to complete positively associated with compliance.

Despite bests efforts to reduce ACL injury risk, ACL injuries still occur, and attention must also be directed to secondary prevention strategies. These include prevention of further ACL injury as well as prevention of post traumatic knee osteoarthritis. In terms of second ACL injury prevention, although numerous risk factors have been identified it is clear that younger athletes who return to pivot and contact sports have high rates of further injury and must therefore be a focus. Return to sport testing has become popular over recent years. It is unclear though whether such testing is designed to determine whether an athlete is capable of returning to sport or determine whether it is safe. Despite the current discussions around return to sport testing following ACL reconstruction, the evidence around it is relatively limited, and the available evidence is somewhat conflicting. A common theme however is that a surprisingly low number of athletes meet return to sport thresholds and criteria with a recent systematic review showing an overall rate of 23% of patients passing return to sport test batteries both prior to and after return to strenuous sports. Caution should therefore be used in applying information gained from current return to sport testing and advising athletes about the risk for further injury.

It has recently been argued that there is no clear evi­dence that current ACL rehabilitation programs include approaches to prevent future de­velopment of knee osteoarthritis and that such an approach should include aggressive knee extensor strengthening, as well as strategies for optimal loading of the vulnerable joint. Patient education should also be a key component to ensure realistic expectations for long term knee heath.

Whilst injury prevention and risk reduction strategies for primary and secondary ACL injury and osteoarthritis has been a focus of current research the challenge remains to extrapolate from this body of evidence to other lower limb musculoskeletal injuries for which data is scarce.

Introduction

Marked quadriceps weakness has been demonstrated prior to undergoing cartilage restoration procedures, and these deficits often persist postoperatively. Blood flow restriction training (BFRT) continues to gain interest amongst rehabilitation specialists as a novel method to improve quadriceps strength. Blood flow restriction training (BFRT) involves the use of an inflatable cuff applied to the thigh to slow blood flow as subjects exercise with a light weight allowing them to receive the same training benefits as if they were training under high loads. The premise for using BFRT after cartilage procedures was initially based off successful use in healthy populations but more recently in patients knee disorders demonstrating greater strength gains than traditional forms of exercise. There is evidence supporting the premise that BFRT will result in both improved quadriceps and hip strength. This then holds promise as greater muscle strength in turn will result in improved lower extremity biomechanics, improved functional capacity, and an accelerated recovery.

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In this presentation, we will discuss the physiologic mechanisms of BFRT. We and others have shown BFRT is able to preferentially improve muscle fiber cross-sectional area, increase satellite cell proliferation and may reduce the extracellular matrix in healthy subjects. We are further motivated by our recently published data in anterior cruciate ligament reconstructed subjects which show that these are the precise properties of muscle that are negatively impacted after the injury and rehabilitation so should be positively altered by BFRT.We have also seen that improved quadriceps strength is associated with reducedfear of re-injury and improved self-reported ability to perform quadriceps-dominant activities such as ascending stairs.

BFRT could potentially benefit those with patellofemoral lesions as well. Increased quadriceps strength has been shown to be protective against patellofemoral cartilage loss as well as less pain and improved function.BFRT may not only result in improved quadriceps strength but also proximal changes in hip strength and muscular characteristics. Hip weakness and increased knee adduction angles increase the forces born by the articular cartilage. Improving quadriceps and hip strength may also be chondroprotective by reducing femoral internal rotation thereby lessening compressive forces borne by the cartilage of the lateral patella and trochlea. BFRT with the cuff placed around the proximal thigh has been demonstrated to improve quadriceps strength but has also resulted in changes proximal to the cuff. In healthy volunteers, thigh girth and hip abduction and external rotation strength have both been shown to have significantly greater improvements following a BFRT program when compared to those that completed the same exercise program without BFRT. In older adults, BFRT has also been demonstrated to increase cross sectional area of the hip adductor and gluteus maximus muscle groups in addition to the quadriceps.

Despite rapid adoption in the clinical setting, there is a great deal of variability in BFRT treatment protocols being used. This variability then results in variable strength gains with BFRT. In a balanced presentation of the literature to date, we will also discuss the treatment protocols that have been the most effective as well as contraindications that must be considered prior to using BFRT.